Washington DC
THERE is no polite way to say this: some scientists claim you have a sex organ up your nose. If the idea disturbs you, don鈥檛 worry too much. Other researchers remain sniffy about the prospect.
The minute structure that the scientists are arguing over is called the vomeronasal organ, or VNO for short. The VNO consists of a pair of tiny dents on either side of the nasal septum, on top of the vomer bone. That same structure in other mammals is clearly a sensory organ, and it often plays a key role both in sex and other social games that animals play. In rats, mice, hamsters, prairie voles and possums, the VNO is used to detect tiny amounts of chemicals called pheromones that the animals release to signal who鈥檚 looking for a mate, who鈥檚 ovulating, and even who鈥檚 fathered whose young.
After decades of denying its existence in humans, anatomists now generally agree that we have a structure that looks suspiciously like a VNO. What鈥檚 at issue is whether the VNO actually does anything in the human or whether it is just a nonfunctioning vestige left over from our four-legged forebears.
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One group, led by David Berliner, cofounder of the Pherin Corporation, a drugs company in Menlo Park, California, says that without a doubt the human VNO is an amazingly sensitive sense organ, and that compounds which stimulate it provoke profound physiological changes in the VNO鈥檚 owner. But many other scientists who study chemical communication between animals remain unconvinced about Pherin鈥檚 more extravagant claims-though they are quick to say that a functional role for the human VNO is not out of the question either.
The pro-VNO researchers say that their disbelieving colleagues, like the anatomists before them, are in denial. After all, if humans turn out to have a functioning VNO the implications are staggering, not to mention a little embarrassing. It would mean that the physiologists had managed to overlook a major sense organ and an important part of our sexual equipment, despite centuries of poking, prodding and dissecting the human body. More ominously, such a sixth sense organ would also reveal a whole new subconscious front in the war between the sexes. Commercial exploitation of the sexual dimension is already under way. A line of perfumes said to contain human pheromones that work by stimulating the VNO is on sale in the US and Europe. Trade is brisk.
Plastic surgeons might also be interested in the veracity of the pro-VNO claims. After all, they routinely remove the VNO when fixing up noses, either totally unaware of its existence, or confident that it won鈥檛 be missed.
But perhaps the most far-reaching implication is that synthetic pheromones, by acting through the VNO, may have the power to treat disorders as varied as prostate cancer and premenstrual syndrome. Pherin has raised at least $9 million from investors on the basis of that hope.
Curiously, the VNO in humans was first spotted around 300 years ago but then mysteriously disappeared from the textbooks. The organ is entirely distinct from the nose鈥檚 main sensor for airborne chemicals, the olfactory epithelium, which detects everyday scents such as those from food and flowers. From the outside, the human VNO looks like two small pits, about a centimetre up from the nostrils, with tiny openings in their centres that are about 0.1 millimetres across. Behind each opening is a short blind tube, which may-or may not-contain working pheromone receptor cells.
Despite the sharp-eyed detective work of the old anatomists, the VNO remained an unexplained oddity for centuries. And when a leading anatomist in the 1930s asserted that though the VNO was present in fetal humans, it was only the rare adult who had one, the organ virtually disappeared from standard anatomy texts.
If the VNOs of humans and animals were first spotted centuries back, their chemical counterparts, the pheromones, only entered research consciousness a few decades ago. The word pheromone was coined in 1959 by scientists studying chemical communication among insects. They applied it to any compound-be it a steroid, alkaloid, protein, or something else-that is released by one member of a species to carry information to another member of the same species.
Because all animals, including bugs, spend a lot of energy on reproduction, it is no surprise that most pheromonal conversations are blatant sexual boasting. And in insects, the barest whiff of a sex pheromone often provokes an all-encompassing response. In their baser moments, for example, scientists have tricked male gypsy moths into copulating with everything from oak leaves to filter paper, just by dousing them with the sublime female gypsy moth scent.
Such sexual shenanigans among insects soon lured pheromone researchers into studying the even more complex chemical ecology of mammals. They noted that pregnant mice abort their fetuses if they are exposed to urine from male mice other than the fetuses鈥� father. They found that male mice emit ultrasonic mating calls in response to the urine of fertile females. And they discovered that male hamsters will copulate with anaesthetised male hamsters who are scented with aphrodisin, a protein pheromone in female hamster vaginal secretions.
They also noticed that many small mammals, including mice and hamsters, stop responding to pheromonal cues if their VNOs are cut out, or if a part of the brain called the accessory olfactory bulb is destroyed. This structure is the first relay station for sensory nerves coming from the VNO, which in turn sends signals to the hypothalamus, an ancient part of the brain that helps regulate feeding, fighting and reproduction, as well as such raw emotions as fear and anger. The findings left no doubt that in the mouse and hamster at least, the VNO is essential for a healthy sex life.
Led by the nose
Still, the fact that some mammals have a sensory sex organ up their noses seemed to have little relevance to humans, who were still assumed to be VNO-less.
That all began to change in 1986, when two researchers set out systematically to check persistent rumours that the human VNO did, after all, exist. Armed only with a Kleenex and a speculum, David Moran, a cell biologist then at the University of Pennsylvania in Philadelphia, and Bruce Jafek, an otolaryngologist at the University of Colorado in Boulder, found vomeronasal pits in virtually all the people they examined.
And when the researchers used an electron microscope to examine tissue from behind the pits that had been removed during plastic surgery, they discovered cells that looked in some ways similar to sensory nerve cells in the rat VNO. In both cases, the cells are shaped like rather fat, bulbous cigars. There was one important difference, however. Neither Moran nor Jafek could detect the axons that would be needed to connect the human VNO cells to the brain.
Mystery extract
Enter Berliner, an anatomy professor turned entrepreneur with a fondness for red Rolls Royces. While studying the chemistry of human skin, Berliner had discovered a mysterious skin extract that, when left open to the air, put his lab workers in uncharacteristically good moods. By the late 1980s, he had recruited some scientific collaborators to help him probe whether the human VNO was involved in these odd mood swings.
One of his collaborators, Luis Monti-Bloch, a physiologist at the University of Utah in Salt Lake City, devised a combination micro-spray and electrode to record changes in the surface voltage of cells that line the VNO while he squirted in different components of the skin extract. Similar electrical probes have long been used to record changes in voltage at the surface of the olfactory epithelium in response to molecules that waft up the nose and stimulate the smell receptors.
Two steroid compounds in the extracts triggered an electrical response in the cells of the VNO, but not in the olfactory epithelium. In other words, they seemed to be detected by the VNO, but not the usual organ of smell. Compounds such as clove oil, which cause a massive change in surface voltage of the olfactory epithelium and have a strong odour, did nothing for the VNO.
Most startling of all, the VNO鈥檚 sensitivity to the two steroids in the skin extract depended on the sex of its owner. The VNOs of male volunteers became electrically excited in response to a steroid found in women鈥檚 skin. The VNOs of women, on the other hand, were excited by a steroid found in men鈥檚 skin.
To Monti-Bloch and Berliner, these results suggested that the human VNO, far from being the nasal equivalent of the appendix, was as vital as any other sense organ. What is more, it seemed to play a role in some type of subliminal sexual signalling.
On that basis, Berliner created a new company, Erox, now based in New York, that sells two perfumes, one for men and the other for women. The advertising bumph makes a lot of the fact that the perfumes contain pheromones, and purchasers tend to assume that the perfume they wear is a sexual attractant to members of the opposite sex. In fact, Realm Men contains the steroid from women鈥檚 skin, while Realm Women contains the steroid from men鈥檚 skin. The company says the purpose of putting women鈥檚 chemicals on men, and vice versa, is to make the wearers feel good and full of confidence. In other words, to give the pheromonal illusion that they have just been bonking.
鈥淗umans release these pheromones from their skin, and they can be sensed only when another person is at a very close range,鈥� explains Berliner. 鈥淪o when a man smells the pheromone from a woman, he feels good. I have said over and over that these are not sex attractants or aphrodisiacs, but somehow people just don鈥檛 listen.鈥� Not to worry. Trade is brisk.
Sexual healing
The confidence of the sales team was boosted by more than perfume in June last year when Berliner鈥檚 team published what it believes is conclusive evidence that the human VNO is indeed active. In an article in the Journal of Steroid Biochemistry and Molecular Biology, they reported that when tiny doses-less than a billionth of a gram-of a synthetic steroid dubbed PDD (pregna-4,20-diene-3,6-dione) were sprayed onto the VNO pits of ten men, they suddenly became laid-back and relaxed. Their heart and breathing rates slowed, while the capillaries in the skin of their hands dilated, and electrical recordings of the brain found an increase in alpha-wave activity, classic signs of relaxation.
But the most important finding, says Monti-Bloch, who is also vice president of experimental research at Pherin, is that PDD squirted onto the VNO altered the daily rhythms of two key hormones, luteinising hormone and follicle-stimulating hormone. On command from the hypothalamus, the pituitary gland releases these hormones into the blood in pulses several times each day. The hormones, in turn, determine a man鈥檚 testosterone levels. Spraying about 200 trillionths of a gram of PDD onto the VNO several times per hour for six hours increased the time between the hormone pulses in men. Female volunteers were unmoved by similar treatment. And according to Monti-Bloch, as yet unpublished data show that the men鈥檚 testosterone levels also fell.
鈥淲e have for the first time been able to manipulate the primitive brain through a nerve connection, using synthetic derivatives of human pheromones that stimulate the human VNO,鈥� claims Berliner, arguing that the steroid doses were so tiny that it is implausible that the steroids had entered the bloodstream and had had an effect that way.
Berliner is also confident that there is an enormous potential for creating drugs that have their impact directly on the VNO. For instance, he says, VNO drugs might one day replace the drugs currently used to reduce testosterone in men with prostate cancer, or to reduce luteinising hormone and testosterone in women with polycystic ovaries.
And there could be big advantages to using drugs that are sprayed directly onto the VNO. Not only would they act extremely quickly, but they may have fewer side effects, because only minute amounts are needed and they do not have to slosh around the bloodstream to reach their target organ.
But perhaps the biggest market for what Berliner dubs 鈥渧omeropherins鈥� would be to treat mood disorders such as acute anxiety by inducing an instant state of relaxation. Pherin has already started a small clinical study at the University of Utah鈥檚 Women鈥檚 Premenstrual Syndrome Clinic in Salt Lake City designed to work out whether a vomeropherin can help alleviate the symptoms of premenstrual syndrome.
Most researchers are noncommittal about Erox鈥檚 enthusiastic claims about the human VNO in its perfume advertising material. Still, whereas perfumeries routinely claim all kinds of magical powers for their products, anyone wanting to market a new drug has to prove that it is both safe and effective-and most researchers are decidedly sceptical about the potential of the human VNO for pharmaceuticals manipulation.
Michael Meredith at Florida State University in Tallahassee, who studies the vomeronasal system in mammals, echoes many others when he says, 鈥渢here鈥檚 no evidence that [the human VNO] is not active, but I still have a lot of questions.鈥� In particular, he says, no one has found the anatomical proof of the nervous connection between the VNO and the brain.
In all fairness, says Meredith, such an experiment is far from simple. Dye would have to be placed on the VNO of a human corpse, while the expectant researcher would have to wait for months for it to seep along the nerve axons to the brain. What鈥檚 more, although the Pherin team is producing exactly the sort of physiological evidence needed to show that the VNO is the seat of a sixth human sense, Meredith makes no bones about the fact that he would be more 鈥渁pt to believe it if it was also corroborated by another source whose fortunes do not rise or fall on the result鈥�.
The nose has it
Molecular biologist Richard Axel of Columbia University College of Physicians and Surgeons in New York City is agnostic too, although last year he found two human genes that are very similar to the rat genes that code for VNO receptor proteins, the docking points for the pheromones. The trouble is, he says, the human genes contain sequences that would lead to the production of foreshortened receptor proteins that very likely wouldn鈥檛 work.
For his part, Berliner is not much concerned with whether other scientists believe in a functional human VNO or not. 鈥淚 work in the pharmaceuticals industry, and it is not my job to worry about whether academics believe in my work or not,鈥� he says. 鈥淭o those who wonder about our results, I say do the studies yourself. Tell us we鈥檙e wrong.鈥�
And what if Berliner鈥檚 team is right? What if he and his colleagues turn out to be genuinely insightful risk-takers, destined to be the first to cash in on the human鈥檚 sixth sense organ? Berliner is on top of that one. Not only will he and his team earn a place in the anatomy textbooks as the discoverers of the human sexual nose, they will also stand to make a great deal of money.
